A "hydrogel" is a crosslinked polymer network which is insoluble in water but swells to an equilibrium size in the presence of excess water. Research on hydrogels started in the 1960s with a landmark paper on poly(hydroxyethyl methacrylate) [Wichterle, O., et al., 1960]. Due to the unique properties of hydrogels and their potential applications in such areas as controlled drug delivery, various types of hydrogels have been synthesized and characterized. Most of this work has focused on lightly cross-linked, homogeneous homopolymers and copolymers.
The bulk polymerization, i.e., polymerization in the absence of added solvent, of monomers to make a homogeneous hydrogel produces a glassy, transparent polymer matrix which is very hard. When immersed in water, the glassy matrix swells to become soft and flexible. Although it permits the transfer of water and some low molecular weight solutes, such a swollen polymer matrix (hydrogel) is considered non-porous. The pores between polymer chains are in fact the only spaces available for the mass transfer, and the pore size is within the range of molecular dimensions (a few nanometers or less) [Chirila, T., et al., 1993]. In this case, the transfer of water or other solutes is achieved by a pure diffusional mechanism, which restricts the rate of absorption and to some extent the size of species that are absorbed [Skelly, P. J., 1979]. Homogeneous hydrogels have been used widely in various applications, especially in the controlled drug delivery area where limited diffusional characteristics are required [Oxley, H. R., 1993].
Porous hydrogels are usually prepared by a solution polymerization technique, which entails polymerizing monomers in a suitable solvent. The nature of a synthesized hydrogel, whether a compact gel or a loose polymer network, depends on the type of monomer, the amount of diluent in the monomer mixture, and the amount of crosslinking agent [Barvic, M. et al., 1967]. As the amount of diluent (usually water) in the monomer mixture increases, the pore size also increases up to the micron range [Chirila, T. et al., 1993]. Hydrogels with effective pore sizes in the 10-100 nm range and in the 100 nm-10 .mu.m range are termed "microporous" and "macroporous" hydrogels, respectively. In practice, the terms "microporous" and "macroporous" are used interchangeably simply due to the fact that there is no unified definition of micro- and macro-pores in hydrogels. Accordingly, hydrogels having pores up to about 10 .mu.m can be called either microporous or macroporous.
Porous hydrogels can be made by preparing hydrogels (usually from polymerizable monomers) in the presence of dispersed water-soluble porosigens, which can be removed later by washing with water to leave an interconnected meshwork (i.e., porous hydrogels) [Oxley, H. R. et al., 1993; Krauch, C. H. et al., 1968]. Examples of effective porosigens are micronized sucrose, lactose, and dextrin [Oxley, H. et al., 1993], sodium chloride [Kon, M. et al., 1981], and poly(ethylene oxides) (PEGs) [Badiger, M. et al., 1993].
Water itself can be used as a porosigen if a polymer network is formed in the frozen state. Monomers can be polymerized in the frozen state around aqueous crystals, and then water can be subsequently removed by thawing to result in a macroporous hydrogel [Oxley, H. R. et al., 1993; Haldon, R. A. et al., 1972]. In this approach, which is appropriately called a "freeze-thaw" technique, ice crystals function as the porosigen. When a polymer network is formed in an aqueous solution, the whole system can be freeze dried to sublimate ice crystals and leave a porous matrix [Loree, H. M. et al., 1989]. This "freeze-drying" technique is useful in the preparation of porous hydrogels from water-soluble polymers such as polysaccharides (e.g., sodium alginate) [Cole, S. M. et al., 1992]. To prepare porous hydrogels more effectively using the freeze-drying technique, salt can be added as another porosigen, and this increases the reproducibility of preparing porous materials [de Groot, J. H. et al., 1990].
Non-aqueous solutions can also be used as porosigens in polymerization of an oil-in-water emulsion system [Gross, J. R., 1995]. In this case, the water phase contains water-soluble monomers and a crosslinker and the oil phase is a volatile organic solvent. The continuous water phase is polymerized and this is followed by evaporation of the oil phase, which results in the porous structure.
The pore size of hydrogels prepared by the porosigen technique depends on the size of the porosigens. The introduction of a porosigen reduces mechanical strength significantly, although a negative effect on the mechanical properties can be minimized if the size of the porosigen is maintained below about 40 .mu.m. In many cases where larger pores are necessary, microparticulate particles (e.g., sucrose crystals) in the range of 100-300 .mu.m can be used [de Groot, J. H. et al., 1990]. The presence of such large sized pores will obviously make the porous hydrogels extremely weak.
In a solution polymerization, the monomers are usually mixed in a diluent which is good for both monomers and polymers. If, however, the diluent is a non-solvent for the polymer formed (e.g., PHEMA in water), the solubility of polymers dramatically decreases as the polymerization proceeds. This results in phase separation of the polymer-rich monomer phase into droplets, which then join together to form a network filled with large spaces (i.e., heterogeneous, porous hydrogels) by the end of the polymerization process. This process is called heterogeneous solution polymerization [Chirila, T. et al., 1993; Barvic, M. et al., 1967; Dusek, K. et al., 1969].
Phase separation can also be induced from the initially homogeneous polymer solution by altering the solvent quality. The solvent quality can be decreased by removing good solvent or adding non-solvent to a polymer solution or by changing the temperature. Many polymer solutions form a reversible gel upon changes in temperature. For example, gelatin in water becomes a gel when cooled below the critical miscibility temperature [Young, A. T., 1985]. In general, aqueous polymer solutions can be rapidly frozen to result in spinodal decomposition, and subsequent removal of water by freeze-dry sublimation yields porous hydrogels.
For polymers with a lower critical solution temperature (LCST), water becomes a non-solvent to the polymer and phase separation occurs as the temperature is increased above the LCST. This technique has been used to prepare porous hydrogels made of poly(N-isopropylpolyacrylamide) [Kabra, B. G. et al., 1991; Yan, Q. et al., 1995; Wu, X. S. et al., 1995], and crosslinked hydroxypropylcellulose [Kabra, B. G. et al., 1994]. The pore sizes of macroporous hydrogels prepared by phase separation are typically only a few micrometers. In addition, the overall porosity is very low and this implies that the pores are not well interconnected. The major limitation of the phase separation method is that only very limited types of porous hydrogels can be prepared. In addition, there is not much control over the porosity of the gels when prepared by phase separation.
Additionally, individual hydrogel particles can be surface crosslinked to form crosslinked aggregates of particles, thereby forming pores between the hydrogel particles. Such aggregate macrostructures are prepared by initially mixing the hydrogel particles (in the range of a few hundred micrometers) with a solution of a crosslinking agent, water, and hydrophilic organic solvent such as isopropanol [Rezai, E. et al., 1994]. Pores in such structures are present between hydrogel particles and the size of the pores is much smaller than the size of the particles. This approach is limited to absorbent particles having chemically active functional groups on the surface.
It is important to distinguish the microporous and macroporous structures of hydrogels with those of non-hydrogel porous materials, such as porous polyurethane foams. In the plastic foam area, micro- and macro-pores are indicated as having pores less than 50 .mu.m and pores in the 100-300 .mu.m range, respectively [de Groot, J. H. et al., 1990]. One of the reasons for this difference is that hydrogels with pores larger than 10 .mu.m were rarely made, while porous plastics having pores in the 100-300 .mu.m range are very common. Porous hydrogels with a pore size larger than 100 .mu.m were made only recently [Park, H. et al., 1994A; Park, H. et al., 1994B], and that is probably why these definitions for porous hydrogels differ from those for porous plastics.
Microporous and macroporous hydrogels are sometimes called polymer "sponges" [Chirila, T. et al., 1993]. When a monomer, e.g., hydroxyethyl methacrylate (HEMA), is polymerized at an initial monomer concentration of 45 (w/w) % or higher in water, a hydrogel is produced with a porosity higher than the homogeneous hydrogels. These heterogeneous hydrogels are sometimes called "sponges" in the biomedical literature [Chirila, T. et al., 1993; Kon, M. et al., 1981]. The term "sponge" is not recommended, however, since it is better known as "rubber sponge" which is not a hydrogel in any sense. Moreover, the properties of rubber sponges are totally different from porous hydrogels. For example, rubber sponges release imbibed water upon squeezing, but porous hydrogels may not be squeezable--they may break into pieces with water entrapped in the polymer networks because of their hydrophilic nature.
U.S. Pat. No. 5,451,613 (issued to Smith et al.), and related patents, proposes making superabsorbent polymers by polymerizing a monomer solution containing carboxylic acid monomers and an effective amount of a crosslinking agent, in the presence of a carbonate blowing agent, to thereby form a microcellular hydrogel. The microcellular hydrogel is then chopped or ground and the pieces are used to form a core polymer. The core polymer is then surface crosslinked to provide superabsorbent particles.
U.S. Pat. No. 5,338,766 (issued to Phan et al.) proposes making a superabsorbent polymer foam from an unsaturated monomer having neutralized carboxyl groups reacted with an internal crosslinking agent. The monomer and crosslinking agent are expanded in the presence of a blowing agent and a solvent so as to form an expanded structure. The expansion and reaction are controlled to form the superabsorbent polymer material.
U.S. Pat. No. 5,154,713 (issued to Lind) proposes forming a superabsorbent polymer by forming a microcellular hydrogel from a (meth)acrylic acid monomer in the presence of a carbonate blowing agent. This material is then chopped into pieces and dried to produce a superabsorbent particulate polymer.
U.S. Pat. No. 4,525,527 (issued to Takeda et al.) proposes making a crosslinked acrylic resin having improved water absorbing properties. The acrylic resin is prepared by aqueous polymerization of acrylic acid, acrylamide, and a water soluble polyvinyl monomer.
One of the limiting factors of hydrogels has been the rather slow swelling property of dried hydrogels. For the dried hydrogels to swell, water has to be absorbed into the glassy matrix of the dried hydrogels. The swelling kinetics of the dried hydrogels thus depend on the absorption of water occurring by a diffusional process and the relaxation of the polymer chains in the rubbery region. Equilibrium swelling of dried hydrogels in an ordinary tablet size (e.g., 1 cm in diameter.times.0.5 cm height) usually takes at least several hours, and this may be too slow for many applications where fast swelling is essential. For example, hydrogels have been successfully used as a gastric retention device that can stay in the stomach of a dog for up to 60 hours [Shalaby, W. S. W. et al., 1992A; Shalaby, W. S. W. et al., 1992B]. In those studies, however, hydrogels had to be preswollen for a few hours before administering to the dog to avoid premature emptying into the intestine.
In an effort to overcome the slow swelling property of dried hydrogels, the present inventors have synthesized a superporous hydrogel that can swell within minutes regardless of the size of the matrix [Chen, J., 1997]. While these superporous hydrogels provided significantly fast swelling kinetics and high swelling extent, the mechanical strength of the fully swollen superporous hydrogels was too poor to be useful. In some cases, the fully swollen superporous hydrogels could not be picked up and broke easily due to their very poor mechanical properties. Usually, mechanically strong superporous hydrogels can be made by increasing the crosslinking density, but this would result in a very small extent of swelling with a loss of the superabsorbent property. Thus, it is desired to make superporous hydrogels having fast swelling and high absorbency characteristics as well as high mechanical strength.